The NDF/heregulins are a known family of molecules which stimulate the tyrosine phosphorylation of the erbB2/Her2 protooncogene product p185; see Peles et al., Cell, Volume 69, pages 1-14 (1992); Wen et al., Cell, Volume 69, pages 559-572 (1992); Holmes et al., Science, Volume 256, pages 1205-1210 (1992); and Bacus et al., Cancer Research, Volume 53, pages 5251-5261 (1993). Thought at first to be ligands for erbB2/Her2, the NDF/heregulins are now known to bind to and stimulate the kinase activity of erbB3/Her3 and erbB4/Her4; see Plowman et al., Nature, Volume 366, pages 473-475 (1993); Kita et al., FEBS Letters, Volume 349, pages 139-143 (1994); and Carraway et al., Journal of Biological Chemistry, Volume 269, pages 14303-14306 (1994). The NDF/heregulin family is considered to also include ARIA and glial growth factor (GGF); see, respectively, Falls et al., Cell, Volume 72, pages 801-805 (1993), and Marchionni et al., Nature, Volume 362, pages 312-316 (1993).
The NDF/heregulins are transmembrane glycoproteins which, in the main, possess an EGF-like domain in the extracellular portion that may function as a receptor recognition site; Wen et al., Cell, above. The original group of NDF/heregulins comprise at least ten isoforms, which can be divided into two groups, called alpha (.alpha.) and beta (.beta.), based on differences in the EGF-like domain. Analysis suggests that the various isoforms are generated by alternative gene splicing and perform distint tissue-specific functions in vivo; Wen et al., Molecular and Cellular Biology, Volume 14, Number 3, pages 1909-1919 (1994).
Several functions of the NDF/heregulins have been identified, including the induction of either mitogenesis or differentiation in mammary cells (Peles et al., Cell, above); the stimulation of muscle acetylcholine receptors (Falls et al., above); and the mitogenesis of Schwann cells (Marchionni et al., above).
Kita et al. in Biochemical and Biophysical Research Communications, Volume 210, Number 2, pages 441-451 (1995), describe a biologically active 52-amino acid peptide which is based on the sequence of the EGF-like domain of NDF-.alpha.2 and is produced by chemical synthesis. The peptide is shown to stimulate tyrosine phosphorylation of Her2, Her3 and Her4, and to induce morphological changes in breast cancer cells.
U.S. Pat. No. 5,670,342 (issued Sep. 23, 1997) describes chemically synthesized peptides which are derived from the sequence of the EGF-like domain of NDF and are active in promoting the growth of both Schwann cells and colon epithelial cells. One of these peptides is a "hybrid" (.alpha./.beta.) molecule composed of sequence from the EGF-like domains of both the alpha(.alpha.) and the beta(.beta.) forms of NDF. See, also, U.S. Pat. No. 5,686,415 (issued Nov. 11, 1997), as well as pending applications Ser. No. 08/761,038 and Ser. No. 08/761,762, both filed Dec. 5, 1996.